The goals of this sub-project are to use x-ray crystallography and other necessary models to learn how control proteins and drug molecules recognize and bind to particular target sites in double-stranded DNA, and how this leads to the control of gene expression. These goals involve structural and biochemical studies of protein/DNA complexes, drug/DNA complexes, and unbound DNA itself. Four projects will be pursued in parallel, in order to learn. 1. How response regulators such as NarL, part of a two-component signaling cascade in bacteria, are activated so that they can bind to specific DNA sites, turning key genes on or off, and why these response regulators bind to selected target sequences but not to DNA in general. The results should be extendable to the multi-component control cascade of higher organisms. 2. How HIV can prevent digestion by RNASE H of the Polypurine Tract primer site for (+)-strand DNA synthesis in an infected cell, and how these protein can be disrupted by drug molecules that bind selective within the Polypurine Tract minor groove. 3. How site-by-side and crosslinked minor groove binding drug molecules can bind selectively to target sequences of B-DNA and how strong and highly selective drug can be prepared to read all four base pairings: AT, TA, GC and CG. This should assist in the design of drugs that can be vectored to specific DNA sites found in the invader but not found in the host. 4. How DNA base sequence determines local variation in helix geometry, of a type that can be used in the recognition of DNA by proteins and drugs.